Zhou Li, Mei Shuai, Ma Xiaozhu, Wuyun Qidamugai, Cai Ziyang, Chen Chen, Ding Hu, Yan Jiangtao
Division of Cardiology, Departments of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Epigenomics. 2025 Jan;17(1):33-48. doi: 10.1080/17501911.2024.2435257. Epub 2024 Dec 2.
Diabetic cardiomyopathy (DbCM), a complex metabolic disease, greatly threatens human health due to therapeutic limitations. Multi-omics approaches facilitate the elucidation of its intrinsic pathological changes.
Metabolomics, RNA-seq, proteomics, and assay of transposase-accessible chromatin (ATAC-seq) were utilized to elucidate multidimensional molecular alterations in DbCM.
In the heart and plasma of mice with DbCM, metabolomic analysis demonstrated significant differences in branched-chain amino acids (BCAAs) and lipids. Subsequent RNA-seq and proteomics showed that the key genes, including BCKDHB, PPM1K, Cpt1b, Fabp4, Acadm, Acadl, Acadvl, HADH, HADHA, HADHB, Eci1, Eci2, PDK4, and HMGCS2, were aberrantly regulated, contributing to the disorder of BCAAs and fatty acids. ATAC-seq analysis underscored the pivotal role of epigenetic regulation by revealing dynamic shifts in chromatin accessibility and a robust positive correlation with gene expression patterns in diabetic cardiomyopathy mice. Furthermore, motif analysis identified that KLF15 as a critical transcription factor in DbCM, regulating the core genes implicated with BCAAs metabolism.
Our research delved into the metabolic alterations and epigenetic landscape and revealed that KLF15 may be a promising candidate for therapeutic intervention in DbCM.
糖尿病性心肌病（DbCM）是一种复杂的代谢性疾病，由于治疗局限性，对人类健康构成重大威胁。多组学方法有助于阐明其内在病理变化。
利用代谢组学、RNA测序、蛋白质组学和转座酶可及染色质分析（ATAC测序）来阐明DbCM中的多维分子改变。
在DbCM小鼠的心脏和血浆中，代谢组学分析显示支链氨基酸（BCAAs）和脂质存在显著差异。随后的RNA测序和蛋白质组学表明，包括BCKDHB、PPM1K、Cpt1b、Fabp4、Acadm、Acadl、Acadvl、HADH、HADHA、HADHB、Eci1、Eci2、PDK4和HMGCS2在内的关键基因受到异常调控，导致BCAAs和脂肪酸紊乱。ATAC测序分析通过揭示染色质可及性的动态变化以及与糖尿病性心肌病小鼠基因表达模式的强正相关，强调了表观遗传调控的关键作用。此外，基序分析确定KLF15是DbCM中的关键转录因子，调节与BCAAs代谢相关的核心基因。
我们的研究深入探讨了代谢改变和表观遗传格局，发现KLF15可能是DbCM治疗干预的一个有前景的候选靶点。
